Obesity is known to be associated with various cancers and hypoadiponectinemia has been also shown to be a risk factor for these obesity-associated cancers 
. Epidemiological evidence of the association between obesity and HCC is also rapidly increasing including patients with HCV infection. In a community-based cohort study, Chen et al. reported that obesity was an independent risk factor for HCC development in anti-HCV-seropositive subjects 
. Therefore, we hypothesized that serum adiponectin level may be associated with the prevalence of HCC in patients with HCV infection. However, in this case-control study, serum total and HMW adiponectin levels were not significantly and inversely associated with the prevalence of HCC. Similarly, Nkontchou et al. also demonstrated that serum level of adiponectin is not predictive of HCC development in patients with compensated HCV cirrhosis 
. In patients with HCV infection, it is well known that metabolic abnormalities such as obesity and diabetes are closely associated with hepatic steatosis 
and severe fibrosis 
; as a result, obesity affect as a partial factor of HCC development. On the other hand, several recent reports have shown that hypoadiponectinemia was associated with hepatic steatosis only in limited genotype 
and association between hypoadiponectinemia and fibrosis progression was not found in patients with HCV infection 
. In addition, we assessed the association between BMI and serum adiponectin levels in cases and controls. Our results showed that these adiponectin levels were not inversely associated with BMI, suggesting that adiponectin is not a cofactor in the development of HCC associated with obesity in patients with HCV infection.
Recently, several studies have been reported that serum adiponectin level was associated with progression of liver fibrosis in patients with chronic liver disease 
. We also evaluated the association between serum total and HMW adiponectin levels and progression of liver fibrosis. APRI is a useful noninvasive marker for the prediction of liver fibrosis in chronic liver disease with HCV infection 
and we assessed the degree of liver fibrosis by APRI in this study. As a result, serum total and HMW adiponectin levels were positively and significantly associated with APRI in both cases and controls. Tietge et al. reported that circulating adiponectin level increased in patients with liver cirrhosis, because of reduced liver function as a major source of adiponectin extraction and altered hepatic hemodynamics 
. Taken together serum total and HMW adiponectin levels may be a predictors of liver fibrosis in patients with HCV infection.
Next, we examined the relationship between serum adiponectin levels and HCC histological grades. Interestingly, low total and HMW adiponectin levels were independent risk factors for worse HCC histological grades. It is generally known that majority of HCC arises as very well-differentiated cancers and proliferate in a stepwise process of dedifferentiation. When small HCC of the early-stage reach around 1.5–2.0 cm, moderately or poorly differentiated cancer tissues develops within the well-differentiated cancer tissue, and well-differentiated cancer tissue are replaced by less differentiated cancer tissue in so-called advanced HCC 
. In this study, the mean tumor size of well-differentiated HCC was 14.2±3.2 mm, which was significantly smaller than the mean size of moderately and poorly differentiated HCC. This result indicated that a dedifferentiation of HCC is associated with tumor proliferation.
This is a cross-sectional study and causal relationship between serum adiponectin level and dedifferentiation of HCC is unclear. One would think that dedifferentiation of HCC may trigger a mechanism which leads to decreased serum adiponectin level. However, it seems that hypoadiponectinemia may trigger dedifferentiation of HCC because of followings: Saxena et al. showed that adiponectin increased the phosphorylation of AMP-activated protein kinase (AMPK) and the TSC2 tumor suppressor, and inhibited phosphorylation of the mammalian target of rapamycin (mTOR) in vitro assay using Huh7 and HepG2 HCC cells 
. Moreover, microarray analysis of tissue adiponectin expression levels in human HCC patients revealed that adiponectin expression was inversely correlated with tumor size 
. Miyazaki et al. showed that adiponectin stimulated c-Jun NH2-terminal kinase (JNK) activation and suppressed signal transducer and activator of transcription 3 (STAT3) activation in HepG2 HCC cells 
. Thus, these studies support that adiponectin level may inhibit proliferation and differentiation of HCC.
Angiogenesis is also an important process for proliferation, dedifferentiation, and metastasis of HCC. In small sized and well-differentiated HCCs, artery-like vessels are not well developed 
. On the other hand, in moderately or poorly differentiated HCCs with 2 cm or larger, artery-like vessels are well developed 
, and these tumors display high proliferation and metastasis so-called advanced stage. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen, and is the most important factor in tumor angiogenesis 
. Yamaguchi et al. showed that VEGF expression in well-differentiated HCC was higher than expression in moderately and poorly differentiated HCC 
. Well-differentiated HCCs that are 1.0–1.5 cm would be in the transitioning from the portal blood supply to an arterial blood supply, which would result in increased VEGF expression because of relative hypoxia from low blood flow. Therefore, high VEGF expression in small-sized and Well-differentiated HCCs suggests that VEGF plays an important role during relatively early angiogenesis stages in HCC. Previous studies have reported on the the molecular mechanisms involved in the negative association of adiponectin with tumor angiogenesis 
. Man et al. showed in an orthotopic liver tumor nude mouse model that adiponectin suppresses tumor growth through inhibition of tumor angiogenesis 
. The molecular mechanism involves adiponectin downregulation of VEGF expression through inhibition of tumor-associated macrophages in tumor tissue. Moreover, the nude mice administrated adiponectin had significantly lower circulating VEGF levels than the control. This result suggests that adiponectin may inhibit dedifferentiation in well-differentiated HCC by inhibition of tumor angiogenesis-related VEGF.
Adiponectin exists mainly in three forms 
. HMW adiponectin is thought to have higher biological activity than the other forms of adiponectin, especially in the liver 
. Several studies have reported that HMW adiponectin levels or the ratio of HMW to total adiponectin is inversely and more strongly associated with metabolic risk factors than total adiponectin levels 
. However, it remains unknown whether HMW adiponectin has more strongly potential actions on cancer pathophysiology than total adiponectin. In this study, we demonstrated that total and HMW adiponectin were independent risk factors for HCC histological grade. However, odds ratio of these factors were similar and serum total adiponectin levels were significantly associated with serum HMW adiponectin levels in this study (data not shown). Thus, one would think that impact of HMW adiponectin may be equal to total adiponectin for predicting HCC histological grade and testing for either total or HMW adiponectin levels may be as effective as testing both levels.
In conclusion, our data suggested that serum total and HMW adiponectin levels were predictors of liver fibrosis, but not prevalence of HCC in patients with chronic HCV infection. Moreover, we showed that low total and HMW adiponectin levels were independent risk factors for worse histological grades of HCC. Further study will be focused on the causal relationship between hypoadiponectinemia and dedifferentiation of HCC.